For the past decade we’ve consistently heard antibiotics don’t work as well as they used to. Bacteria are becoming increasingly resistant to their effects and we are approaching a time when many bacteria could be resistant to all the antibiotics we have.

Apocalyptic premonitions of the post-antibiotic era aside, what is being done about it? The World Health Organisation recommends a number of different measures. High on the list is renewing efforts to discover and develop blockbuster agents that can combat these new “superbugs”.

Lower down the list are recommendations about how to use antibiotics more responsibly. This means having strategies in place to help preserve the remaining effective antibiotics.

Any use of antibiotics encourages exposed bacteria to develop ways of becoming resistant. Exposing bacteria to antibiotics pressures them to adapt to the antibiotics in an “adapt or die” life and death saga. This is called selection pressure.

Bacteria under threat from antibiotics eventually come up with a way of overcoming their vulnerability. They may develop thicker or more repellent membranes to stop antibiotics from getting into the bacterial cell in the first place. Bacteria may switch on or turn up pumps to expel any antibiotic that does get into the cell. These are just some of the tricks they have to become antibiotic resistant.

Part of ensuring we preserve the antibiotics we have left is to reduce the development of resistance. One way to do this is by replacing antibiotics with agents that kill micro-organisms, but aren’t actually antibiotics. These are called non-antibiotic antimicrobials.

Non-antibiotic bacteria killers

Antibiotics are chemicals that can inhibit the growth of, or kill, bacteria. They generally have one way to inhibit or kill bacteria and can usually be taken internally, say orally or intravenously. They are toxic only to bacteria and not to the patient.

Like antibiotics, non-antibiotic antimicrobials also inhibit and kill bacteria. However, unlike antibiotics, they often have multiple ways of killing or inhibiting bacteria, and are often toxic if ingested. They are frequently limited to topical applications such as creams and ointments. Antiseptics are classic non-antibiotic agents.

Many antibiotics are used topically to prevent infections such as those on the skin. While they do this quite effectively, exposing bacteria to antibiotics encourages the processes that lead to antibiotic resistance. Using non-antibiotic antimicrobials instead of antibiotics can help reduce antibiotic resistance.

Some non-antibiotics

Honey

As part of a larger study into keeping dialysis patients healthy, researchers found medical-grade honey was as effective as a topical antibiotic cream they had used around catheter sites to stop infections starting. They also noted that the level of resistance to the antibiotic they previously used declined once they stopped using it.

Mannose

Recent trials in humans (see here and here) have suggested that mannose, a type of sugar similar to glucose, may be useful in the treatment of urinary tract infections. Mannose, found in many fruits and vegetables, was found to render bacteria incapable of attaching to the cells of the urinary tract.

Trisodium citrate

Doctors working with kidney dialysis patients in the 1990s identified a simple salt, trisodium citrate, that could help keep the patients’ catheters (thin tubes inserted into the skin to drain fluid or administer drugs) from becoming blocked. A secondary effect, serendipitously observed later, was that its use also led to lower rates of infection.

In the almost two decades since, and largely through the efforts of non-commercial interests, trisodium citrate has become one of the main strategies used globally for preventing catheter-related bloodstream infections in dialysis patients.

Tea tree oil

Tea tree oil inhibits and kills a wide range of bacteria and is safe for topical use. Tea tree oil has also been found to be effective against some antibiotic-resistant bacteria.

Vinegar

Peritoneal dialysis patients, who permanently have a catheter in their abdominal cavity, sometimes develop infections on the skin around the permanent catheter. If the infection is caused by the notoriously antibiotic-resistant bacterium Pseudomonas aeruginosa, it can be difficult to treat and lead to the loss of the catheter and the end of that type of dialysis for the patient.

Bathing the site with a dilute solution of vinegar can help resolve this otherwise difficult-to-treat infection. The acidity of the vinegar due to its acetic acid content is thought to be responsible for its effectiveness.

Why aren’t we doing this?

In order to be substituted for antibiotics, there must be evidence that the non-antibiotic agent is as effective as antibiotics and is safe. The evidence would come from laboaratory-based work and clinical trials, which cost money to generate. Usually this work is done by companies that patent the product, pay the costs of development and then benefit from the market monopoly the patent gives them.

Many non-antibiotic antimicrobial agents such as those discussed above are not products that can be patented. Thus no drug companies can make money from their use. Consequently, the work either happens very slowly or doesn’t get done at all.

So despite the potentially enormous health, social and economic benefits that may flow from their development and use, including the preservation of antibiotics, there is almost no commercial incentive to develop and test them and few efficient non-commercial pathways.

Antibiotics are a precious, rapidly waning resource that should be preserved for as long as possible. Substituting non-antibiotic agents for antibiotics, if proven safe and effective, would mean that bacteria would be less likely to develop resistance. Then if and when they are really needed, antibiotics would still work.

In the 1950s, German company Chemie Grünenthal developed a “wonder drug” sleeping pill that it marketed around the world as safe for everyone, including expectant mothers. This mild sedative was also found to mitigate the effects of morning sickness, resulting in increased use by the population that turned out to be most vulnerable to its risks.

Shortly after the drug came on the market, reports of infant deaths and startling birth malformations were made worldwide. Grünenthal rigorously denied thalidomide’s association with these adverse effects for a long time.

It took until 1962 for the pill to be banned in most countries and decades of extensive legal battles ensued. More than half a century later, the thalidomide crisis is continuing to shed insights on pharmaceutical ethics, scientific integrity and professional wrongdoing.

Scientists are people too

Fifty-six years after the first known victim of thalidomide was born to a Grünenthal employee, the company’s chief executive officer Harold Stock issued an apology, which did little to appease victims.

Stock said Grünenthal researchers had conducted all possible tests on thalidomide based on latest science. This is directly contradicted by the work of Dr Frances Kelsey, who in 1960, despite pressure from supervisors at the Food and Drug Administration (FDA), refused thalidomide’s application for sale in the United States.

She noted important gaps in the data used to support the claim that thalidomide was safe for pregnant women. Kelsey’s training in pharmacology helped her notice the lack of evidence. So if Kelsey saw the obvious shortfalls in thalidomide’s safety profile, then what did Grünenthal scientists know, or ought to have known?

Conventional wisdom suggests that scientists do science; that they are specially trained professionals who conduct research in a way that systematically explores the unknown, minimises bias, and reaches beyond assumptions using latest information and technology.

Whether they work in universities or pharmaceutical companies, scientists are supposed to be governed by scientific principles before anything else. Kelsey demonstrated this principle when she resisted pressure from above. But given her heroine status, this may be the exception and not the norm.

For pragmatic scientists who depend on their employment or research funding, these principles could be compromising. Relaxing them can be rationalised as normal or acceptable, with hidden biases taking root and impacting how they conduct research and subsequent results.

Subtle decisions (often perfectly legal) can distort medical research and corrupt scientific knowledge. With most of us believing we are “good people”, it follows that scientists may resist acknowledging their subtle shifts in approach and there are always reasons to explain it away.

Grünenthal’s alleged “omit then deny” strategy fits this perfectly.

By not conducting the tests Kelsey inquired about, Grünenthal could free itself from evidence that would limit its market for the drug. By claiming it was not normal practice to test for the effects of medications on developing fetuses, Grünenthal could argue against any obligation to conduct these tests.

Indeed, the claim that these tests were uncommon formed one of the pillars upholding Grünenthal’s denial of responsibility.

Corporate culture and Nazi war crimes

Some have speculated that Grünenthal’s culture was tainted because several World War II Nazi war criminals – including Otto Ambros, a scientist found guilty of mass murder at the Nuremberg trials – had been employed there.

But how much should we rely on this “bad apple” narrative when trying to make sense of the thalidomide crisis?

The reality is that many pharmaceutical companies have and continue to be fined, charged, and accused of unethical behaviour related to production and marketing of their drugs.

The scientists who conduct research on these drugs and become tied up in unethical practices are less often like Nazi war criminals, and more often like us. They take pride in their work and have no intention to harm others. But they face pressures that lead to compromises with implications they may choose not to consider.

Complicating matters is the unique set of risks faced by scientists who speak up for public safety against the wishes of their funders or superiors. In doing so, they risk their reputations, employment and future funding opportunities.

German paediatrician Dr Widukund Lenz was allegedly threatened with legal action by Grünenthal after he suggested a possible link between thalidomide, while it was still being sold, and birth deformities.

Allegations have also been made that Grünenthal attempted to corrupt science by blocking medical publications. In one case, they were allegedly successful at convincing a medical journal to purposely delay publication of an article by neurologist Dr Horst Frenkel that demonstrated thalidomide’s negative side effects. Again, the drug was still being sold at this time.

Attempting to corrupt the scientific process is not something unique to this particular pharmaceutical company. In fact, attacks on scientists and attempts to distort science are a growing concern.

The story of Canadian scientist Nancy Olivieri especially highlights the tremendous personal costs scientists face speaking up for public safety. The drug company partially funding Olivieri’s research (that planned to market the drug after trials) threatened her with legal action if she followed through on her ethical obligation to inform patients and the scientific community the drug she was testing on them was potentially toxic and could be ineffective.

But, like Kelsey, Olivieri went ahead despite “severe consequences”. She received the 2009 AAAS Award for Scientific Freedom and Responsibility for her “… determination that patient safety and research integrity come before institutional and commercial interests”.

What now?

More than half a century after the thalidomide crisis, we are still haunted by the opportunity for compromised science.

Just this year, doctors raised red flags on another popular drug for morning sickness (called Diclectin in Canada and Diclegis in the United States) that is being prescribed in as many as 50% of live births in some countries.

Concerned experts claim the published results on Diclectin overstate its benefits, understate its risks, and ignore safer (and cheaper) vitamin alternatives.

Research integrity and the institutional structures that support scientific research are key to understanding and eliminating scientific compromises. Without this understanding, we can’t truly progress beyond the “Grünenthal science” that underscored the thalidomide tragedy.